The present invention relates to methods for the topical treatment of rosacea.
Rosacea is a common chronic skin condition characterized by a spectrum of clinical indications including flushing episodes, erythema, telangiectasia, inflammatory papulopustular eruptions resembling acne, and ocular symptoms. Although accurate incidence data for the U.S. are not available, data obtained in Sweden suggest that some form of rosacea may be present in up to 10% of the average population. Sufferers are mostly of European origin, generally with fair skin and blue eyes. Women are more prone to develop rosacea than men, with flushing episodes and erythema being the most common symptoms found.
The etiology of rosacea is unknown, but it is presumed to be a genetically determined anomalous vascular response that develops in the third to sixth decades of life. The hypothesis that the basic pathogenesis of the disease is a flushing disorder is based on several findings. The disease appears to more prevalent in northern climates where cold exposure is experienced more often, and in light-skinned persons in whom flushing is common and sensitivity to sunlight is particularly high. Accordingly, rosacea may represent a type of hypersensitivity reaction disease in which vascular sensitivity is a central mechanism in its etiology. The correlation between sensitive blood vessels and sensitive skin has, however, not yet been determined. Epidemiological studies suggest that the regulatory mechanism of blood vessels may be of importance in the onset and development of rosacea. Studies show that 27% of rosacea patients were found to suffer from migraine and 42% from a tendency to flush, both of which represent about twice the level that would typically be found in a control group.
An etiological role has also been proposed for the Demodex species, mites that normally inhabit human hair follicles and are reported to appear in greater numbers in rosacea patients. A number of dietary factors, for example hot drinks, alcohol, spicy foods, and environmental conditions (e.g., temperature changes), are well-recognized triggers of the disease. In literature, there are also reports of possible involvement of altered immune function and anomalously low skin surface lipids in the pathogenesis of rosacea.
The key to successful management of rosacea is early diagnosis and treatment. Treatment is generally aimed at controlling the symptoms and making the skin look better. At the present time, rosacea cannot be cured, though the frequency of its flare-ups can be diminished and their severity alleviated. Most cases of rosacea can be controlled with anti-inflammatory medications, combined with the avoidance of lifestyle and environmental factors that may aggravate the disorder in individual cases. Treatment generally works best at improving the pimples and bumps of rosacea; the redness of the skin is harder to treat. Therapeutic agents for inflammatory rosacea conditions are generally classified in two groups: (1) systemic and topical antibiotics; and (2) retinoids. Systemic and topical antibiotics include tetracycline, metronidazole, erythromycin, minocycline and clindamycin, but the use of these agents is often accompanied by drug side effects, the development of resistance, and changes in the normal microbial flora. Retinoids include tretinoin (vitamin A or retinoic acid), which is applied topically to inhibit follicular keratinization, and isotretinoin (13-cis-retinoic acid), which is administered systemically to suppress activity of the sebaceous glands. Retinoids are often irritants and are not advised for individuals with sensitive skin. Retinoids can also be phototoxic and they can induce thin and easily bruisable, fragile skin.
Metronidazole (5-methyl-5-nitroimidazole-1-ethanol), an antibacterial, is currently one of the more frequently prescribed treatments for rosacea in the United States. It is available as a topical cream under the name Metrogel(trademark) from Galderma. Metronidazole is structurally similar to some materials which are believed to be carcinogens and is, in fact, listed by the U.S. Environmental Protection Agency as reasonably anticipated to be a human carcinogen. See Merck Index, 1996, page 1051.
Thus, there is a need for a safe and effective topical treatment of the symptoms of rosacea which not only act quickly and effectively, but which present reduced side effects when compared to the current treatment modalities.
Methods for treating rosacea have been described in the patent literature. Recent examples include the following patents.
U.S. Pat. No. 5,932,215, De Lacharriere, et al., issued Aug. 3, 1999, describes a method for the topical and systemic treatment of rosacea using an antagonist of CGRP (calcitonin gene-related peptide).
U.S. Pat. No. 5,972,993, Ptchelintsev, issued Oct. 26, 1999, describes a method for treating rosacea and sensitive skin conditions using certain specifically-defined antioxidant materials.
U.S. Pat. No. 5,952,372, McDaniel, issued Sep. 14, 1999, describes a method for treating rosacea using oral or topically applied ivermectin. This method of treatment is aimed at reducing or eliminating the Demodex organisms which are frequently found on the skin of rosacea patients.
U.S. Pat. No. 5,654,312, Andrulis, Jr., et al., issued Aug. 5, 1997, describes a method for the systemic or topical treatment of inflammatory or autoimmune dermatoses using thalidomide, either alone or in combination with a cytokine inhibitor or a growth factor inhibitor.
U.S. Pat. No. 5,998,395, Kligman, issued Dec. 7, 1999, describes a method for suppressing inflammation in an inflammatory dermatosis, such as rosacea, using a topically applied composition containing both a corticosteroid and a retinoid.
U.S. Pat. No. 6,028,118, Dupont et al., Feb. 22, 2000, describes the use of a shark cartilage extract as an anti-angiogenic, anti-inflammatory and anti-collagenolytic material which may be used in the treatment of rosacea.
U.S. Pat. No. 5,994,330, El Khoury, issued Nov. 30, 1999, describes the treatment of acne and other inflammatory skin conditions using topically administered muscarinic agents. The therapeutic effects of the invention are said to include a decrease in redness, swelling and inflammation.
U.S. Pat. No. 5,968,532, De Lacharriere, et al., issued Oct. 19, 1999, describes the use of an ethylene diamine derivative in a cosmetic or dermatological composition containing a material having an irritant side effect. The ethylene diamine derivative is said to minimize skin irritation, erythema and sensations of inflammation or rosacea stemming from the use of the cosmetic/dermatological product.
U.S. Pat. No. 6,071,955, Elias, et al., issued Jun. 6, 2000, describes the use of juvenile hormone III to treat acne or acneiform conditions. The compounds is said to act as an activator of the receptors XFR, PPARA and LXRA.
U.S. Pat. No. 5,885,595, Corey, et al., issued Mar. 23, 1999, describes a cosmetic composition which includes a retinol fatty acid ester. The composition is said to be effective for treating chronoaging conditions of the skin and dermatological disorders including acne, follicular and lesional papules, actinic keratoses, oily skin and rosacea.
U.S. Pat. No. 5,895,649, De Lacharriere, et al., issued Apr. 20, 1999, describes a method for treating neurogenic red skin blotches, including those present with rosacea, using the topical application of a TNF-alpha antagonist.
U.S. Pat. No. 6,071,541, Murad, issued Jun. 6, 2000, describes the use of a topical composition which contains a hydroxy acid or tannic acid to exfoliate a portion of the skin, stabilized hydrogen peroxide to facilitate cleansing of the skin, and an antimicrobial agent to inhibit or reduce microorganisms on the skin. The composition is said to be effective in the treatment and management of inflammatory skin conditions, such as acne and acneiform rosacea.
U.S. Pat. No. 5,972,892, De Lacharriere, et al., issued Oct. 26, 1999, describes a therapeutic composition for topical application containing at least one material having an irritant side effect together with a substance P antagonist for reducing or eliminating the irritant effect of this material. The substance P antagonist may be a peptide compound or a nitrogen-containing compound or a nitrogen-, sulfur- or oxygen-containing heterocyclic compound.
U.S. Pat. No. 6,057,341, Charpentier, issued May 2, 2000, describes pharmaceutical or cosmetic compositions which include novel bi-aromatic dibenzofuran derivatives. The compositions are said to exhibit pharmacological responses of the retinoid agonist type and are further said to be effective in treating keratinization disorders, including acne rosacea.
U.S. Pat. No. 6,054,475, Martin, et al., issued Apr. 25, 2000, describes the use of substituted dihydrobenzofuran-based phosphodiesterase-4 inhibitors for the treatment of proliferative, inflammatory and allergic dermatoses, including acne rosacea.
U.S. Pat. No. 6,057,453, Yang, et al., issued May 2, 2000, and U.S. Pat. No. 6,060,604, Yang, et al., issued May 9, 2000, describe a novel class of polyamines substituted with electron-affinic groups. These materials are said to be effective in the treatment of dermatological conditions caused by anaerobic and microaerophilic microorganisms.
Organic alcohols, diols and polyols have been disclosed for use in the treatment of a variety of dermatological conditions.
U.S. Pat. No. 6,290,937, Brown, et al., issued Sep. 18, 2001, and which has been withdrawn from issue by the Patent Office, described a series of pharmaceutical compositions which were said to increase the melanin content of mammalian melanocytes and which were also said to be useful for treating skin proliferative disorders, such as acne vulgaris. The compositions disclosed may utilize C3-C50 diols as the pharmaceutically active agent; 1,2-cis- and 1,2-trans-cyclohexanediol are specifically disclosed as active ingredients. In addition, 1,2-cis-cyclopentanediol was among the preferred active compounds. The treatment of rosacea was not disclosed or suggested. Since this patent has been withdrawn from issue, it does not constitute prior art.
U.S. Pat. No. 6,184,422, Barbier, et al., issued Feb. 6, 2001, discloses a group of unsaturated long-chain (for example, C12) derivatives of cyclohexanediol. These materials are taught to be useful topically for the treatment of hyperproliferative diseases and diseases of the sebaceous glands, such as acne. See also related U.S. Pat. No. 5,969,190.
U.S. Pat. No. 5,886,233, Steinmeyer, et al., issued Mar. 23, 1999, describes cyclohexanone derivatives used to synthesize vitamin D compounds. The compounds are said to be useful for treating skin, such as in the treatment of acne.
U.S. Pat. No. 6,277,837, DeLuca, Jr., et al., issued Aug. 21, 2001, describes a group of vitamin D-related compounds which include a cyclohexanediol moiety. The compositions are taught to be useful for the treatment of cell proliferation diseases, such as psoriasis. See also related U.S. Pat. Nos. 6,127,559; 5,945,410; 5,936,133; and 5,843,928.
U.S. Pat. No. 5,641,809, Hagen, et al., issued Jun. 24, 1997, describes a skin treatment composition that includes lanolin together with an ester of a lanolin acid. The patent teaches that lanolin includes C9-C22 diols as one of its components. The treatment of rosacea is not disclosed or suggested.
The present invention relates to a method of treating rosacea in humans comprising topically applying to a patient in need of such treatment a safe and effective amount (for example, from about 0.05 to about 1 mg/cm2) of the compound having the following formula, at the site of said rosacea or where said patient is prone to exhibit rosacea: 
wherein R1 is selected from xe2x80x94OH and C1-C3 alkyl OH (alkanols), and R2, R3, R4, R5 and R6 are each independently selected from xe2x80x94H, xe2x80x94OH, C1-C6 alkyl and C3-C6 cycloalkyl.
Particularly preferred compounds are cyclohexanol, 1,2-cyclohexanediol, 1,3-cyclohexanediol, and 1,4-cyclohexanediol, and mixtures of those materials. The active material may be administered with a pharmaceutical carrier.
The present invention also encompasses a method for treating acne vulgaris in humans comprising topically applying to the affected site of a patient in need of such treatment a safe and effective amount of an active compound defined herein, such as 1,3-cyclohexanediol, 1,4-cyclohexanediol, and mixtures thereof.
Finally, the present invention encompasses the treatment of conditions characterized by inflammatory or allergy symptoms, such as colds, flu, sinusitis, and ear infections, by the topical application of an effective amount of the active materials defined herein.
All percentages and ratios given herein are by weight, unless otherwise specified.
All patents and other publications cited in this application are incorporated herein by reference.